The present invention relates to the synthesis of cyclitols and derivatives thereof from substituted arene diols.
Cyclitols are polyoxyfunctional (i.e., having 2 to 6 hydroxy, alkoxy, aryloxy or phosphate functionalities) cyclohexane derivatives, and as such are classified as carbohydrates [Anderson, In The Carbohydrates Chemistry and Biochemistry, Pigman et al., Eds., Academic Pres: New York, Vol. la, Chap. 15, 1972]. All possible stereoisomers of these compounds are known to occur in nature (seven meso forms and one DL pair). Indeed, cyclitols appear to be present, both free and combined, in the tissues of nearly all living species [Posternak, T. The Cyclitols, Hermann: Paris, 1962]. Dihydroconduritols are a subclass of inositols in which the number of hydroxyl groups present is reduced to four. These compounds, along with conduritols (cyclohexenetetrols) are of interest because of their potential use as inhibitors for glycosidases [Postermak, T. The Cyclitols, Hermann: Paris, 1962].
Previous syntheses of these types of compounds have started from achiral sources and have either involved numerous steps, incomplete stereospecificity at some point, or did not lead to optically pure products [Posternak et al., Helv. Chim. Acta 36:251, 1953; Gorin, Can. J. Chem. 42:1749, 1964; Nakajima et al., S. Ber. 92:173, 1959]. Benzene-cis-diol has been used in a number of natural product syntheses [Carless et al., Tetrahedron Lett. 30:3113, 1989; Carless et al., Tetrahedron Lett. 30:1719, 1989]. Ley et al used the benzene diol to synthesize (+)-pinitol [Tetrahedron Letters 45:3463, 1989] and myo-inositol triphosphate [Tetrahedron Letters 29:5305, 1988]. One obvious disadvantage to using benzene-cis-diol in natural product synthesis, however, is the preclusion of enantiocontrolled synthesis without further (usually enzymatic) manipulations of the meso intermediates. For this and other reasons, the methods of the present invention utilize optically pure chiral synthons resulting from microbial oxidation of monosubstituted benzene derivatives.
Other syntheses of cyclitols are disclosed in Balci, M. et al., Tetrahedron 1990, 46, 3715; Secen et al., Tetrahedron Lett. 31:1323, 1990; Akbulut et al., J. Org. Chem. 53:3338, 1988; Sutbeyaz et al., J. Chem. Soc. Commun. 1330, 1988; Bruce et al., Tetrahedron Lett. 30:7257, 1989; Kobayashi et al., J. Org. Chem. 55:1169, 1990; and Gorin, Canadian J. Chem. 42:1748, 1964.
In 1970 Gibson and co-workers reported the enantioselective oxidation of toluene to cis-toluenediol [(+)-cis-2,3-dihydroxymethylcyclohexa-4,6-diene] by a mutant of Pseudomonas putida, a soil bacterium [Gibson et al., J. Biochemistry 9:1626 (1970)]. Since that time many other simple arenes were shown to yield diols of this type through microbial oxidation techniques [Jerina et al., Arch. Biochem. Biophys. 142:394 (1971); Gibson et al., Biochemistry 7:3795 (1968); Jeffrey et al., Biochemistry 14:575 (1975); Burlingame et al., J. Bacteriol. 168:55 (1986); Gibson et al., Biochem. Biophys. Res. Commun. 50:211 (1973); Gibson et al., J. Bacteriol. 119:930 (1974); Whited et al., J. Bacteriol. 166:1028 (1986); Ziffer et al., Tetrahedron 33:2491 (1977)].
Despite the operational simplicity and complete stereospecificity of the reaction producing such diols, little use of this transformation has been made in organic synthesis, save for a few recent reports. Hudlicky et al [J. Am. Chem. Soc. 110:4735 (1988)] used the toluene diol to synthesize enones useful for prostaglandin synthesis, aldehydes which are potential synthons for perhydroazulene terpenes, and cyclohexene oxide which is the descarbobenzoxy derivative of crotepoxide. Hudlicky et al [J. Org. Chem. 54:4239 (1989)] have also used the styrene diol to synthesize zeylena, another cyclohexene oxide. However, the full potential of such diols for synthesis of chiral synthons has not yet been fully realized.